Effect of estrogen and progesterone on nerve conduction studies during ovarian cycle

Objectives: This study aims to investigate the effects of estrogen and progesterone on nerve conduction studies (NCSs) in three different hormonal phases of the ovarian cycle. Patients and methods: Between April 2008 and July 2008, a total of 40 healthy volunteer women (mean age: 24.1±5.1 years; range 21 to 43 years) with regular menstrual cycles were included in this prospective study. The participants were regularly menstruating for at least one year, without any hormonal disease and without taking any medication that could lead to hormonal dysregulation. Motor and sensory conduction velocities, amplitudes, and distal latencies were analyzed at the dominant extremities within the early follicular phase (EFP), late follicular phase (LFP), and the midluteal phase (MLP). Results: Except for the median nerve motor conduction velocity (MCV), there were no statistically significant differences between the peripheral NCS results in the three ovarian cycle phases (p=0.033). After adjusting for multiple comparisons, a significant difference was found between the EFP and LFP (p=0.004). Conclusion: Our study results showed that only median nerve MCV was affected in the menstrual cycle. However, this would be an incidental finding, or an increased sensibility of the median nerve motor fibers to ovarian steroids by an unknown mechanism. Further studies are warranted.

Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons' signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

Female Reproductive Strategies and the Ovarian Cycle in Hamadryas Baboons

<p>This thesis examines the relationship between sexual behaviour and the ovarian cycle in a group-living primate, Papio h. hamadryas. Of particular interest is whether females modify their ovarian cycle in a manner that is expected increase their reproductive success. The study was conducted on a captive colony where the resident males (RM) had been vasectomised prior to start of the study resulting in all mature females undergoing repeated ovarian cycling throughout the study period. This made the analysis of sexual behaviour relative to fine scale changes in the ovarian cycle possible. One year of ovarian cycle data and 280 hours of behavioural data was collected via observational sampling during the study. RM vasectomisation did not alter the archetypal one male unit social structure nor the typical socio-spatial organisation of wild hamadryas populations. Females were found to be more promiscuous than in wild populations, however, presumably because of the confounding effect that the high number of simultaneously cycling females had on RM herding (Chapter 1). RMs dominated copulations over the optimal conceptive period of the ovarian cycle, while the majority of extra-OMU copulations occurred outside this period and were rarely solicited by females. This pattern supports a dual paternity concentration/paternity confusion strategy, and not female choice or fertility insurance strategies (Chapter 2). Females were not found to synchronise or asynchronise their cycles over the 1 year study period, although a review of the literature on hamadryas breeding patterns suggests that they may be able to do so over shorter periods (Chapter 3). Females did, however, appear to regulate the length of the turgescent phase of their ovarian cycle in a manner that would facilitate a paternity confusion strategy and maximise their expected fitness payoff (Chapter 4). Consequently, this study provides empirical evidence that female hamadryas baboons manipulate their ovarian cycle in a manner that is expected to increase their reproductive success.</p>

Female Reproductive Strategies and the Ovarian Cycle in Hamadryas Baboons

<p>This thesis examines the relationship between sexual behaviour and the ovarian cycle in a group-living primate, Papio h. hamadryas. Of particular interest is whether females modify their ovarian cycle in a manner that is expected increase their reproductive success. The study was conducted on a captive colony where the resident males (RM) had been vasectomised prior to start of the study resulting in all mature females undergoing repeated ovarian cycling throughout the study period. This made the analysis of sexual behaviour relative to fine scale changes in the ovarian cycle possible. One year of ovarian cycle data and 280 hours of behavioural data was collected via observational sampling during the study. RM vasectomisation did not alter the archetypal one male unit social structure nor the typical socio-spatial organisation of wild hamadryas populations. Females were found to be more promiscuous than in wild populations, however, presumably because of the confounding effect that the high number of simultaneously cycling females had on RM herding (Chapter 1). RMs dominated copulations over the optimal conceptive period of the ovarian cycle, while the majority of extra-OMU copulations occurred outside this period and were rarely solicited by females. This pattern supports a dual paternity concentration/paternity confusion strategy, and not female choice or fertility insurance strategies (Chapter 2). Females were not found to synchronise or asynchronise their cycles over the 1 year study period, although a review of the literature on hamadryas breeding patterns suggests that they may be able to do so over shorter periods (Chapter 3). Females did, however, appear to regulate the length of the turgescent phase of their ovarian cycle in a manner that would facilitate a paternity confusion strategy and maximise their expected fitness payoff (Chapter 4). Consequently, this study provides empirical evidence that female hamadryas baboons manipulate their ovarian cycle in a manner that is expected to increase their reproductive success.</p>

P–606 A second stimulation in the same ovarian cycle rescues advanced-maternal-age patients obtaining ≤ 3 blastocysts after the conventional approach by preventing treatment-discontinuation

Study question Is double stimulation in the same ovarian cycle (DuoStim) a valuable strategy to rescue advanced-maternal-age patients obtaining ≤ 3 blastocysts for chromosomal-testing after conventional stimulation? Summary answer DuoStim is effective to prevent treatment discontinuation thereby increasing the 1-year cumulative-live-birth-rate among advanced-maternal-age patients obtaining 0–3 blastocysts after a first conventional stimulation. What is known already Folliculogenesis is characterized by continuous waves of follicular growth. DuoStim approach exploits these dynamics to conduct two stimulations in a single ovarian cycle and improve the prognosis of advanced-maternal-age and/or reduced-ovarian-reserve women. Independent groups worldwide successfully adopted DuoStim with various regimens reporting similar oocyte/embryo competence after both stimulations. Recently, we have demonstrated the fruitful adoption of DuoStim in patients fulfilling the Bologna criteria, especially because of the prevention of treatment discontinuation. Here we aimed at investigating whether DuoStim can be adopted to rescue poor prognosis patients obtaining 0–3 blastocysts after the conventional approach. Study design, size, duration Proof-of-concept matched case-control study. All patients obtaining 0–3 blastocysts after conventional-stimulation between 2015–2018 were proposed DuoStim. The 143 couples who accepted were matched for maternal age, sperm factor, cumulus-oocyte-complexes and blastocysts obtained after the first stimulation to 143 couples who did not. The primary outcome was the 1-year cumulative-live-birth-rate. If not delivering, the control group had 1 year to undergo a second attempt with conventional-stimulation. All treatments were concluded (live-birth achieved or no euploid left). Participants/materials, setting, methods Only GnRH-antagonist with recombinant-gonadotrophins and agonist trigger stimulation protocols were adopted. All cycles entailed ICSI with ejaculated sperm, blastocyst culture, trophectoderm biopsy, comprehensive-chromosome-testing and vitrified-warmed euploid single-embryo-transfer(s). Cumulative-live-birth-rate was calculated per patient considering both stimulations in the same ovarian cycle (DuoStim group) or up to two stimulations in 1 year (control group). Treatment discontinuation rate in the control group was calculated as patients who did not return for a second stimulation among non-pregnant ones. Main results and the role of chance Among the 286 couples included (41.0±2.9yr;4.9±3.1 cumulus-oocytes-complexes and 0.8±0.9 blastocysts), 126 (63 per group), 98 (49 per group), 52 (26 per group) and 10 (5 per group) obtained 0,1,2 and 3 blastocysts after the first stimulation, respectively. The cumulative-live-birth-rate was 9% in the control group after the first attempt (N = 13/143). Among the 130 non-pregnant patients, only 12 returned within 1-year (165±95days later;discontinuation rate=118/130,91%), and 3 delivered. Thus, the cumulative-live-birth-rate from two stimulations in 1-year was 11% (N = 16/143). In the DuoStim group, the cumulative-live-birth-rate was 24% (N = 35/143; Fisher’s-exact-test&lt; 0.01,power=80%). The odds-ratio of delivering in the DuoStim versus the control group adjusted for all matching criteria was 3.3,95%CI:1.6–7.0,p&lt;0.01. This difference (0%,22%,15% and 20% in the control versus 10%,31%,46% and 40% in the DuoStim group among patients obtaining 0,1,2 and 3 blastocysts at the first stimulation, respectively) is mainly due to treatment discontinuation in the control group (98%,65%,77% and 80% among patients obtaining 0,1,2 and 3 blastocysts at the first stimulation, respectively) and the further increased maternal age at the time of second retrieval (∼6 months). Notably, 2 patients delivered 2 live-births after DuoStim (none in the control) and 14 patients with a live-birth have euploid blastocysts left (2 in the control). Limitations, reasons for caution Randomized-controlled-trials and cost-effectiveness analyses are desirable to confirm these data. Moreover, 75% of the patients included were &gt;39yr and 44% obtained no blastocyst after the first stimulation. Therefore future studies among younger women and/or more women obtaining ≥1 blastocyst are advisable to set reasonable cut-off values to apply this strategy. Wider implications of the findings: A second stimulation in the same ovarian cycle might be envisioned as a rescue strategy for poor IVF outcomes after a first stimulation, so to prevent treatment discontinuation and increase the cumulative-live-birth-rate. This is feasible since 6–7 days span the first and the second stimulation in the DuoStim protocol. Trial registration number none